Ringman John M, Goate Alison, Masters Colin L, Cairns Nigel J, Danek Adrian, Graff-Radford Neill, Ghetti Bernardino, Morris John C
Mary S. Easton Center for Alzheimer's Disease Research, David Geffen School of Medicine at University of California, Los Angeles, 10911 Weyburn Ave., #200, Los Angeles, 90095-7226, CA, USA,
Curr Neurol Neurosci Rep. 2014 Nov;14(11):499. doi: 10.1007/s11910-014-0499-8.
Since the original publication describing the illness in 1907, the genetic understanding of Alzheimer's disease (AD) has advanced such that it is now clear that it is a genetically heterogeneous condition, the subtypes of which may not uniformly respond to a given intervention. It is therefore critical to characterize the clinical and preclinical stages of AD subtypes, including the rare autosomal dominant forms caused by known mutations in the PSEN1, APP, and PSEN2 genes that are being studied in the Dominantly Inherited Alzheimer Network study and its associated secondary prevention trial. Similar efforts are occurring in an extended Colombian family with a PSEN1 mutation, in APOE ε4 homozygotes, and in Down syndrome. Despite commonalities in the mechanisms producing the AD phenotype, there are also differences that reflect specific genetic origins. Treatment modalities should be chosen and trials designed with these differences in mind. Ideally, the varying pathological cascades involved in the different subtypes of AD should be defined so that both areas of overlap and of distinct differences can be taken into account. At the very least, clinical trials should determine the influence of known genetic factors in post hoc analyses.
自1907年首次发表关于该疾病的描述以来，对阿尔茨海默病（AD）的遗传学认识不断进步，如今已明确它是一种基因异质性疾病，其亚型对特定干预措施的反应可能并不一致。因此，关键在于明确AD各亚型的临床和临床前期阶段，包括由PSEN1、APP和PSEN2基因已知突变引起的罕见常染色体显性形式，这些正在显性遗传阿尔茨海默病网络研究及其相关二级预防试验中进行研究。在一个携带PSEN1突变的哥伦比亚大家庭、APOE ε4纯合子以及唐氏综合征患者中也在开展类似的研究。尽管产生AD表型的机制存在共性，但也存在反映特定遗传起源的差异。在选择治疗方式和设计试验时应考虑到这些差异。理想情况下，应明确AD不同亚型中涉及的不同病理级联反应，以便既能考虑到重叠部分，也能考虑到明显的差异。至少，临床试验应在事后分析中确定已知遗传因素的影响。
